Cutaneous T-cell lymphoma (CTCL) represents a blood cancer that originates in the skin. Unfortunately, this disfiguring malignancy continues to be incurable. The etiology of this disease remains to be elucidated. The lymphoma grows in an environment that includes a spectrum of non-malignant immune cells. Rather than destroying the cancer, the non-malignant cells appear to foster its growth. There is compelling evidence that the immunologic response against the cancer is blunted by inhibitory molecules. However, the specific signals that create a permissive microenvironment are unknown. It is suspected that the expression of microRNAs that regulate gene expression, and their targets known as immune checkpoint molecules such as PD1 and PD-L1, help create the permissive environment in CTCL. Overall, changes in checkpoint expression patterns have been reported in other malignancies and are associated with alterations in the microenvironment, yet their roles have not been extensively studied in CTCL. Very little is known about the use of checkpoint inhibitors in the treatment of this disease, but the investigators' early experience with blockade of the PD1/PD-L1 interaction showed encouraging outcomes. In addition, the investigators have clinical experience with lenalidomide, an immunomodulatory drug that may also affect the interaction of the lymphoma with its microenvironment. On the basis of the preliminary studies, a phase I/II clinical trial investigating the safety and efficacy of durvalumab, an inhibitor of the PD- L1/PD1 tumor interaction, alone or with lenalidomide, is being conducted, with highly promising and safe results to date. These two agents also showed a favorable safety profile in a multiple myeloma trial. In Aim 2, the quantitative characterization of the dysregulated immunophenotypic profile in CTCL will be determined using advanced microscopy techniques (multispectral imaging, high resolution microscopy), and serum and skin pro- inflammatory cytokines will be correlated with response. In Aim 3, preclinical experiments are designed to identify mechanisms that dictate expression of critical immune checkpoint regulators. It is expected that baseline immune checkpoint and/or miRNA signatures will be linked to anti-tumor response and that down- regulation of the aberrant immune checkpoint expression in CTCL will have therapeutic benefits. It is anticipated that PD1/PD-L1 blockade will decrease cancer growth and will correlate with reversal of the permissive microenvironment. The compelling preliminary data provide rationale for this project with correlative aims important determinants toward understanding which patients are likely to respond to therapy, so that this immunotherapy in the future can be selected for those individuals who most likely benefit from this treatment. In addition, mechanistic insights gained from the preclinical studies will identify potential new targets and pathways to enhance the efficacy of this planned therapeutic approach. CTCL is a unique model to study the microenvironment, allowing for multi-site and serial sampling of patients tumors with minimal morbidity, and thus represents a paradigm for dissecting susceptibility and resistance to checkpoint inhibition therapy.